Chronic Obstructive Pulmonary Disease (COPD) due to smoking is the most common lung-related cause of death, and thus one of the most pressing healthcare problems facing our nation. Acute exacerbations of COPD (AE-COPD) are responsible for most of the healthcare costs and much of morbidity and decline in health-related quality of life in COPD. Because current therapies are inadequate to prevent AE-COPD in frequent exacerbators, the underlying reasons for AE-COPD must be better understood. There is no currently accepted computer or animal models of AE-COPD. Hence, samples obtained from human subjects with COPD must be studied. The long-term objective of this project is to understand how elements of the innate and adaptive immune system interact on encountering respiratory viruses, bacterial pathogens, or airborne particulates to induce the symptoms of AE-COPD. This project will correlate the frequency, severity and duration of AE-COPD with analysis of innate and adaptive pulmonary immune functions. The Central Hypothesis is that AE-COPD result from the interaction of hyperactive alveolar macrophages, recruited immature dendritic cells, and persistently-active T cells already resident in the lung parenchyma. Subjects will be a prospective cohort of GOLD stage 3-4 COPD patients with a history of frequent exacerbation who will be followed longitudinally, COPD patients identified at the time of an exacerbation, and control subjects (GOLD 0-1 current and ex-smokers, and never-smokers). Samples will include induced sputum, peripheral blood, lung tissue removed at the time of clinically-indicated surgery, and in selected subjects, bronchoalveolar lavage. These samples will be analyzed by ELISA, realtime PCR, flow cytometry, and immunohistochemistry. RELEVANCE: Chronic Obstructive Pulmonary Disease (COPD) is a common problem in smokers that causes intermittent periods of worsened shortness of breath, cough and increased sputum production ("exacerbations"). The goal of this study is to learn how specific parts of the immune system cause these symptoms. This information is a first step to finding more effective treatments to prevent and treat COPD exacerbations.